Our long-term goal is to understand how macrophages and inflammation contribute to the pathogenesis of type 2 diabetes mellitus. Recent studies clearly show that obesity, a world wide epidemic, is associated with a chronic state of low grade inflammation and various co-morbidities, including insulin resistance, dyslipidemia, hypertension and coronary artery disease. Increased adiposity results in infiltration of adipose tissue by macrophages, which elaborate various pro-inflammatory molecules to promote insulin resistance. However, the regulatory factors and transcriptional networks that control resolution of macrophage-mediated inflammation remain poorly understood. Therefore, studies proposed in the present grant application will investigate the functions of Th2 cytokines and macrophage-mediated inflammation in obesity-induced insulin resistance. Notably, our preliminary data show that biasing of the immune response towards the Th2 axis can attenuate tissue inflammation and enhance insulin sensitivity. To elucidate the molecular mechanisms for the anti-diabetic actions of Th2 cytokines, transgenic, whole-body and tissue-specific knockout mice will be evaluated for their susceptibility to diet-induced insulin resistance. Insights derived from these studies should delineate whether skewing of the immune response and polarization of the macrophages towards the Th2 axis is sufficient to ameliorate insulin resistance in obese animals, thereby paving the way for development of new therapeutics to treat this chronic inflammatory disease. The specific aims of this proposal are to: 1) Determine the role of Th2-type responses in glucose homeostasis, 2) Assess the regulatory role of Th2-type signaling pathways in maintenance of hepatic insulin sensitivity, and 3) Determine whether polarization of macrophages towards the Th2 axis can ameliorate obesity-induced insulin resistance. Relevance: The alarming increase in the rate of obesity has fueled an epidemic of insulin resistance and type 2 diabetes mellitus in the United States. This life-long disease is destined to have a tremendous negative impact on the health of our society. Thus, our studies are aimed at identifying new therapeutic targets that can improve the action of insulin, and limit or delay the onset of type 2 diabetes mellitus.